Reconstructing AF-Associated Atrial Fibrosis: Patient-Specific iPSC Models, Fit-for-Purpose Atrial Microphysiological Systems, and Nanomedicine

Atrial fibrillation (AF)-associated fibrosis is a heterogeneous component of atrial cardiomyopathy that contributes to conduction slowing, anisotropy, reentry susceptibility, and reduced therapeutic responsiveness. However, translation of anti-fibrotic strategies remains limited by the biological heterogeneity of AF and by models that incompletely reproduce human atrial cell composition, mechanics, perfusion, and electrophysiology. This narrative review critically evaluates the convergence of patient-specific induced pluripotent stem cell (iPSC) models, biomimetic atrial-on-a-chip platforms, and nanomedicine. We distinguish direct atrial or AF-specific evidence from cardiac but non-atrial studies and from engineering principles extrapolated from extracardiac fibrosis or oncology. Direct evidence supports chamber-validated iPSC-derived atrial cardiomyocytes, structured cardiomyocyte-fibroblast cocultures, and selected chamber-specific vascularized atrial microtissues for interrogating electrical and fibrotic phenotypes. In contrast, fully integrated patient-specific systems that combine chamber-specific cells, vascular perfusion, controlled mechanical loading, immune components, multiparametric functional readouts, and nanomedicine testing remain at an early stage. We therefore position atrial-on-a-chip platforms as fit-for-purpose, high-content experimental systems for mechanistic comparison and candidate prioritization, rather than as established substitutes for in vivo physiology or clinical trials. Nanocarrier design may address delivery barriers involving biodistribution, dense extracellular matrix, cellular uptake, and endosomal escape; nevertheless, most supporting evidence is currently cardiac non-atrial or extracardiac, and atrial selectivity requires direct validation. By linking evidence level, model capability, assay quality control, delivery performance, and functional safety, this review proposes a staged framework for investigating AF-associated fibrosis and for defining the experiments required before clinical translation.